Autoimmune Encephalomyelitis And Regulatory T Cells

自身免疫性脑脊髓炎和调节性 T 细胞

• 批准号: 8577267
• 负责人: Youhai H Chen
• 金额: $ 37.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-25 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577267
• 关键词: Adoptive Transfer; Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autoimmune Diseases; Automobile Driving; Biochemical; Boxing; Cell Differentiation process; Cell Nucleus; Cell Therapy; Cell physiology; Cells; Central Nervous System Diseases; Chronic; Combined Modality Therapy; Complex; Cytoplasm; Development; Disease; Elements; Exhibits; Experimental Autoimmune Encephalomyelitis; Family; Gene Expression; Genes; Genetic; Health; Human; Immune system; Immunity; Immunologics; Immunosuppression; Infection; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Lymphocyte Subset; Lymphoid; Modeling; Multiple Sclerosis; Mus; Myelin; Nerve Tissue; Nuclear; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Play; Proteins; Regulatory T-Lymphocyte; Risk Factors; Role; Specificity; Staging; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Effect; Therapeutic Uses; Tissues; Transfusion; United States; clinical practice; dosage; gain of function; loss of function; member; new therapeutic target; prevent; programs; public health relevance; relating to nervous system

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. An ideal anti-inflammatory therapy for MS should be one that is neural antigen-specific, i.e., it suppresses only inflammatory cells that cause neural tissue injury but not those that protect against infections. Recently, major advances have been made in our understanding of a naturally occurring lymphocyte subset called regulatory T (Treg) cells that are used precisely by the immune system to perform antigen-specific immunosuppression. They play indispensable roles in maintaining health since their deficiency in mice and humans causes fatal inflammatory diseases. They may also be directly involved in the pathogenesis of MS since their functions and numbers are significantly reduced in patients studied by several groups. More importantly, a number of laboratories including ours have shown that adoptive transfer of myelin-specific Treg cells effectively prevents and ameliorates experimental autoimmune encephalomyelitis, a model for MS, in a myelin-specific manner, not affecting immunity against unrelated antigens. These new advances have led to the recognition that transfusion of myelin-specific Treg cells represents an ideal form of adoptive cell therapy for MS. However, Treg cells are still among the least understood T cell subsets, and consequently the most difficult to use for therapeutic applications. This proposal is inspired by recent discoveries from several laboratories including ours that c-Rel, the lymphoid member of the nuclear factor-?B family and a risk factor for human inflammatory diseases, is a key controller of Treg cell development and function. The objectives of this proposal are to (i) determine how c-Rel turns on Foxp3 gene to initiate Treg cell differentiation, (ii) determine how Foxp3 terminates c-Rel activity to stabilize Treg cell function and (iii) develop a new combination therapy for autoimmune encephalomyelitis by targeting the c-Rel-Foxp3 axis.

描述（由申请人提供）：多发性硬化症 (MS) 是一种中枢神经系统炎症性疾病，仅在美国就有大约 400,000 人患病。多发性硬化症的理想抗炎疗法应该是神经抗原特异性的疗法，即它仅抑制引起神经组织损伤的炎症细胞，而不抑制那些防止感染的炎症细胞。最近，我们对一种称为调节性 T (Treg) 细胞的天然淋巴细胞亚群的理解取得了重大进展，免疫系统精确地使用该细胞来执行抗原特异性免疫抑制。它们在维持健康方面发挥着不可或缺的作用，因为小鼠和人类缺乏它们会导致致命的炎症性疾病。它们也可能直接参与多发性硬化症的发病机制，因为在几组研究的患者中，它们的功能和数量显着减少。更重要的是，包括我们在内的许多实验室已经表明，髓磷脂特异性Treg细胞的过继转移可以以髓磷脂特异性的方式有效预防和改善实验性自身免疫性脑脊髓炎（多发性硬化症的一种模型），而不影响针对无关抗原的免疫力。这些新进展使人们认识到，髓磷脂特异性 Treg 细胞的输注代表了多发性硬化症过继性细胞疗法的理想形式。然而，Treg 细胞仍然是人们最不了解的 T 细胞亚群之一，因此最难用于治疗应用。这一提议的灵感来自于包括我们在内的多个实验室的最新发现，即 c-Rel（核因子-βB 家族的淋巴成员，也是人类炎症性疾病的危险因素）是 Treg 细胞发育和功能的关键控制器。该提案的目标是（i）确定c-Rel如何开启Foxp3基因以启动Treg细胞分化，（ii）确定Foxp3如何终止c-Rel活性以稳定Treg细胞功能，以及（iii）通过靶向c-Rel-Foxp3轴开发一种新的自身免疫性脑脊髓炎联合疗法。